Due to triplication and overexpression of the gene for amyloid precursor protein and other genes on chromosome 21, individuals with Down Syndrome (DS) show neuropathologies of AD at an earlier age than the typical population, and about half of adults with DS develop AD. Yet there is wide phenotypic variation in adults with DS and many do not develop AD. This study proposes to use previously biobanked samples towards identifying factors that contribute to resilience to AD in adults with DS. The project will reprogram established fibroblast lines from older DS subjects with and without concomitant AD into induced pluripotent stem cells (iPSCs) and then differentiate these iPSCs into neurons and then into cortical organoids (mixed cortical neuron and astrocyte 3D culture). These organoids will be used to perform transcriptomic analysis and to examine differences in neuronal development and function. Specifically, this project will use a subset of the biobanked samples that examined over 500 adults with DS longitudinally to investigate DS-AD. We will: (1) reprogram established fibroblasts lines from older DS subjects with or without DS-AD into iPSCs, and then use these iPSCs to investigate: (1) the effects of neuronal development on DS-AD; (2) differential gene expressions and eQTL; and (3) the role of a novel gene, WWOX, in DS-AD. This study will generate resources that will enable researchers to perform functional genomic studies following identification of protective and putative genes in DS-AD.